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Title: EXTL2 and EXTL3 inhibition with siRNAs as a promising substrate reduction therapy for Sanfilippo C syndrome
Author: Canals Montferrer, Isaac
Benetó, Noelia
Cozar, Mónica
Vilageliu i Arqués, Lluïsa
Grinberg Vaisman, Daniel Raúl
Keywords: Malalties hereditàries
Mutació (Biologia)
Genètica molecular humana
Malalties neurodegeneratives
Genetic diseases
Mutation (Biology)
Human molecular genetics
Neurodegenerative Diseases
Issue Date: 2015
Publisher: Nature Publishing Group
Abstract: Sanfilippo syndrome is a rare lysosomal storage disorder caused by an impaired degradation of heparan sulfate (HS). It presents severe and progressive neurodegeneration and currently there is no effective treatment. Substrate reduction therapy (SRT) may be a useful option for neurological disorders of this kind, and several approaches have been tested to date. Here we use different siRNAs targeting EXTL2 and EXTL3 genes, which are important for HS synthesis, as SRT in Sanfilippo C patients' fibroblasts in order to decrease glycosaminoglycan (GAG) storage inside the lysosomes. The results show a high inhibition of the EXTL gene mRNAs (around 90%), a decrease in GAG synthesis after three days (30-60%) and a decrease in GAG storage after 14 days (up to 24%). Moreover, immunocytochemistry analyses showed a clear reversion of the phenotype after treatment. The in vitro inhibition of HS synthesis genes using siRNAs shown here is a first step in the development of a future therapeutic option for Sanfilippo C syndrome.
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It is part of: Scientific Reports, 2015, vol. 5, p. 13654
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ISSN: 2045-2322
Appears in Collections:Articles publicats en revistes (Genètica, Microbiologia i Estadística)

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